Microfluidic systems have found application in various technical fields including biotechnology, chemical processing, medical diagnostics, energy, electronics, and others. Often, microfluidic systems are developed by the technologies of microelectromechanical systems (MEMS) and implemented on various substrates using the fabrication methods similar to those for integrated circuitry. Such systems have been developed for applications including, for example, analysis and detection of polynucleotides or proteins, analysis and detection of proteins, assays of cells or other biological materials, and PCR (polymerase chain reaction amplification of polynucleotides). These systems are commonly referred to as lab-on-a-chip devices.
Various systems and methods of manipulating the fluids within a microfluidic system have been devised and disclosed. Several examples of mechanical mechanisms that have been used include piezoelectric, thermal, shape memory alloy, and mechanical positive displacement micropumps. These types of pumps utilize moving parts which may present problems related to manufacturability, complexity, reliability, power consumption and high operating voltage.
Fluid handling devices without moving parts have also been utilized. Examples of such systems have used devices which manipulate fluids using electrophoresis, electroosmosis, dielectrophoresis, magnetohydrodynamics, and bubble pumping. Electrokinetic mechanisms (i.e., electrophoresis and electroosmosis) are limited because certain operating liquids contain ionic particles. Moreover, they require high voltage and high energy dissipation, and are relatively slow. Likewise, magnetohydrodynamics and thermal bubble pumping require relatively high power to operate.
Handling of fluids in discrete volumes with a microfluidic system has also been reported. Often called digital microfluidics or droplet microfluidics, this approach of handling fluids, mostly as liquid droplets in air or in oil and rarely as gas bubbles in liquid, popularly uses the principle of electrowetting. Electrowetting refers to the principle whereby the surface wetting property of a material (referred to herein as “wettability”) can be modified between various degrees of hydrophobic and hydrophilic states by the use of an electric field applied to the surface.
Electrowetting on a dielectric-coated conductive layer has been used because of its reversibility and has been termed electrowetting-on-dielectric or “EWOD” systems. The EWOD device operates to manipulate fluid droplet by locally changing the surface wettability of the electrowetting surface in the vicinity of the fluid by selectively applying voltage to electrodes under a dielectric film in the vicinity of the fluid. The change in surface wettability causes the shape of the droplet to change. For example, if an electrical potential is applied to an electrode adjacent to the location of the droplet, thereby causing the surface at the adjacent location to become more hydrophilic, then the droplet will tend to be pulled toward the adjacent location. As another example, if voltages are applied to electrodes on two adjacent sides of a droplet, the adjacent surfaces tend to pull the droplet apart, and under proper conditions, the droplet can be divided into two separate droplets.
These electrowetting dynamics can be used to manipulate liquids in several useful ways, including creating a droplet from a liquid reservoir, moving a droplet, dividing or cutting a droplet, and mixing or merging separate droplets. With the ability to controllably perform these types of functions on liquid droplets, a useful microfluidic system is realized.
However, similar fluid manipulations can be obtained, on a similar or often the same device, by other but related actuation mechanisms such as electrostatic and dielectrophoresis (DEP).
For the droplet or digital microfluidic systems to operate effectively, droplet volume uniformity is essential. Attempts to use electrical switching circuitry without feedback can generate droplets with some reasonable accuracy, but it cannot overcome the random errors that are created by the chips and operating conditions. Attempts have been made in some devices to integrate feedback controls with real-time volume detection and signal changing to dispense uniform droplets such as those disclosed in U.S. Pat. Nos. 5,422,664 and 6,719,211. Still others have proposed a feedback control scheme that dispenses liquid on chip using capacitance measurement that is on chip but an external pump connected from off chip. See H. Ren, R. B. Fair, and M. G. Pollack, “Automated on-chip droplet dispensing with volume control by electro-wetting actuation and capacitance metering,” Sensors and Actuators V, Vol. 98, pp. 319-327 (2004).
There is a need, however, for a feedback control system integrated with the pumping on chip, where the generation of uniform volume droplets may be controlled on-chip without the need for external means. A preferred system would employ an “on-chip” feedback system using relatively small and portable electronic circuitry that avoids large and bulky external components. The control system should be rapid enough to permit real-time feedback control so that the droplet volume may be precise. The control system should be all electronic and reprogrammable so that changes may be made “on the fly” to control drop size.